Frontotemporal Dementia (FTD) Research Group Papershttp://hdl.handle.net/2429/35034

2015-03-31T21:20:58ZClinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p (Issued:2012-03)http://hdl.handle.net/2429/44123
Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4 %) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly-recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.
2012-03-01T00:00:00ZFET proteins in frontotemporal dementia and amyotrophic lateral sclerosis (Issued:2012)http://hdl.handle.net/2429/44122
Mutations in the fused in sarcoma gene (FUS) cause amyotrophic lateral sclerosis (ALS) with TDP-43-negative, FUS-positive pathology. FUS is also the pathological protein in most tau/TDP-43-negative subtypes of frontotemporal lobar degeneration (FTLD-FUS). FUS, together with Ewing’s sarcoma protein (EWS) and TATA-binding protein associated factor 15 (TAF15), make up the FET family of DNA/RNA binding proteins that share functional homology and have the potential to interact. We recently investigated the role of the other FET proteins in the clinicopathological spectrum of FUS-opathies. In all FTLD-FUS subtypes, FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins. In contrast, in cases of ALS-FUS, TAF15 and EWS remained localized to the nucleus and did not label FUS-positive inclusions. Cell culture models replicated the human diseases. These findings indicate that ALS-FUS and FTLD-FUS have different pathomechanisms and add TAF15 and EWS to the growing list of RNA-binding proteins involved in neurodegeneration.
2012-01-01T00:00:00ZPathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations : two distinct patterns correlating with disease severity and mutation (Issued:2011-07)http://hdl.handle.net/2429/39941
Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of
familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions
of the associated neuropathology are few and largely restricted to individual case reports. To
better define the neuropathology associated with FUS mutations, we have undertaken a
detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial
cases, with both juvenile and adult onset, and with four different FUS mutations. We found
significant pathological heterogeneity among our cases, with two distinct patterns that
correlated with the disease severity and the specific mutation. Frequent basophilic inclusions
and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a
consistent feature of our early-onset cases, including two with the p.P525L mutation. In
contrast, our late-onset cases, that included two with the p.R521C mutation, had tangle-like
NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments
demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the
neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed
significant differences and suggests that FUS mutations are associated with a distinct
pathobiology.
2011-07-01T00:00:00Z